Temporal analysis of prevalence and antibiotic-resistance patterns in Stenotrophomonas maltophilia clinical isolates in a 19-year retrospective study

Stenotrophomonas maltophilia is a nonfermenting gram-negative bacterium associated with multiple nosocomial outbreaks. Antibiotic resistance increases healthcare costs, disease severity, and mortality. Multidrug-resistant infections (such as S. maltophilia infection) are difficult to treat with conventional antimicrobials. This study aimed to investigate the isolation rates, and resistance trends of S. maltophilia infections over the past 19 years, and provide future projections until 2030. In total, 4466 patients with S. maltophilia infection were identified. The adult and main surgical intensive care unit (ICU) had the highest numbers of patients (32.2%), followed by the cardiology department (29.8%), and the paediatric ICU (10%). The prevalence of S. maltophilia isolation increased from 7% [95% confidence interval (CI) 6.3–7.7%] in 2004–2007 to 15% [95% CI 10.7–19.9%] in 2020–2022. Most S. maltophilia isolates were resistant to ceftazidime (72.5%), levofloxacin (56%), and trimethoprim-sulfamethoxazole (14.05%), according to our study. A consistent and significant difference was found between S. maltophilia-positive ICU patients and non-ICU patients (P = 0.0017) during the three-year pandemic of COVID-19 (2019–2021). The prevalence of S. maltophilia isolates is expected to reach 15.08% [95% CI 12.58–17.59%] by 2030. Swift global action is needed to address this growing issue; healthcare authorities must set priorities and monitor infection escalations and treatment shortages.


Temporal analysis of prevalence and antibiotic-resistance patterns in
Stenotrophomonas maltophilia is a nonfermenting gram-negative bacterium associated with multiple nosocomial outbreaks.Antibiotic resistance increases healthcare costs, disease severity, and mortality.Multidrug-resistant infections (such as S. maltophilia infection) are difficult to treat with conventional antimicrobials.This study aimed to investigate the isolation rates, and resistance trends of S. maltophilia infections over the past 19 years, and provide future projections until 2030.In total, 4466 patients with S. maltophilia infection were identified.The adult and main surgical intensive care unit (ICU) had the highest numbers of patients (32.2%), followed by the cardiology department (29.8%), and the paediatric ICU (10%).The prevalence of S. maltophilia isolation increased from 7% [95% confidence interval (CI) 6.3-7.7%] in 2004-2007 to 15% [95% CI 10.7-19.9%] in 2020-2022.Most S. maltophilia isolates were resistant to ceftazidime (72.5%), levofloxacin (56%), and trimethoprimsulfamethoxazole (14.05%), according to our study.A consistent and significant difference was found between S. maltophilia-positive ICU patients and non-ICU patients (P = 0.0017) during the three-year pandemic of COVID-19 (2019-2021).The prevalence of S. maltophilia isolates is expected to reach 15.08% [95% CI 12.58-17.59%]by 2030.Swift global action is needed to address this growing issue; healthcare authorities must set priorities and monitor infection escalations and treatment shortages.
Stenotrophomonas maltophilia is a nonfermenting gram-negative bacillus 1 found in several environmental reservoirs, including plants, soil, and animals 2 .In addition, it is widely distributed in the environment as a commensal organism, and its impact on severe diseases has been observed on a global scale 1 .It is a pathogenic microorganism responsible for nosocomial infections in individuals with compromised immune systems, specifically healthcare-associated pneumonia in the intensive care unit (ICU) settings 3,4 .Hospital water pipes, sinkholes, and catheters are potential sources of disease transmission 1 .From a clinical perspective, S. maltophilia causes a variety of diseases, including respiratory tract infection (pneumonia), bone and joint infection, bloodstream infection (BSI), meningitis, and urinary tract infection (UTI) 5,6 .Most β-lactams, fluoroquinolones, aminoglycosides, and trimethoprims are ineffective against S. maltophilia because of the bacterium's intrinsic resistance to these classes of antibiotics.Managing infections caused by S. maltophilia is complicated by the fact that the organism is resistant to many antibiotics 7 , a trait known as multidrug resistance (MDR).Furthermore, various clinical laboratories have reported the emergence of pandrug-resistant (PDR) strains of S. maltophilia.These strains are resistant to all available antimicrobial medications.This might be attributed to the improper use of antibiotics, especially broad-spectrum antibiotics 8,9 .S. maltophilia infections are often treated with trimethoprim-sulfamethoxazole (SXT); levofloxacin (LVX) may be used as a secondary option.Ceftazidime (CAZ) and ticarcillin-clavulanate (TIM) are potential therapeutic options.Nonetheless, the previous use of antibiotics may hasten the development of resistant bacteria 10,11 .
However, an increase in the incidence of MDR bacteria, particularly S. maltophilia, has been documented among hospitalised coronavirus disease 2019 (COVID-19) patients owing to the overuse of antimicrobial agents during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which emerged in China in 2019 12,13 .The resistance characteristics of S. maltophilia in Saudi Arabia and the neighbouring region have been the subject of limited research amidst the COVID-19 pandemic.In light of this, the current study aimed to examine the historical pattern of S. maltophilia detection and resistance trends in the last 19 years (2004-2022)  and investigate the forecast of infections until 2030.

Descriptive analysis of the data collected
A total of 4466 patient records of S. maltophilia infections were obtained.The adult and main surgical ICU (AD/ MSICU) had the highest proportion of reported cases (32.2%), followed by a combination of other departments including but not limited to family medicine clinics, eye clinic, orthopaedics Clinics, immunology diseases clinic, nephrology clinic, colorectal clinic, and otolaryngology clinic (29.8%), and the cardiology ward (15.9%).An estimated 10.8% of the patients were reported in the paediatric ICU (Table 1).The number of samples tested was lowest between 2004 and 2007.In 2021, the largest number of samples collected (9.5%), followed by 2019 (7.6%).From 2004 to 2007, the prevalence of S. maltophilia infection was 7%

Antibiotic susceptibility of S. maltophilia isolates
The criteria used for the interpretation of the susceptibility test results adhered to the guidelines established by the CLSI.Table 2 presents the distribution of susceptibility testing findings according to the antibiotics used, categorised by year and the related number of cases.However, except for SXT, most antibiotics were not consistently accessible over all 19 years.Ceftazidime was accessible in all years, except in 2014, 2015, and 2016.LVX was accessible for the entire duration, except in 2004-2007, 2010, and 2011.TIM was administered only in 2017

Effects of COVID-19 pandemic on S. maltophilia infections
The rates of S. maltophilia infection were studied in ICU and non-ICU patients.The overall number of admissions before and during the COVID-19 pandemic was also determined.A significant difference was found between the proportion of ICU patients with positive S. maltophilia cultures and that of non-ICU patients (P = 0.0017) within 3-years, including 2019, 2020, and 2021 (Fig. 4).Furthermore, a statistically significant difference was seen between the numbers of ICU and non-ICU S. maltophilia-positive isolates in the years 2019 and 2021 (P = 0.0372 and P = 0.0033, respectively).It is noteworthy that the number of non-ICU patients with S. maltophilia isolates before and after the pandemic (in 2018 and 2022, respectively) exceeded the number of ICU patients with S. maltophilia isolates in the same period.

Current trend and future forecast
One of the objectives of this study is to use linear regression analysis in order to investigate the chronological patterns of S. maltophilia cases identified throughout the period from 2004 to 2022.The results of the linear regression analysis indicated a statistically significant positive correlation, as shown by the strong coefficient (R 2 = 0.65, P < 0.001).The forecast model, developed using the Prophet package inside the R programming language shows a projection of forthcoming instances, demonstrating a discernible rising trajectory in the number of cases (Fig. 5).

Discussion
According to the available data, this study presents the most extensive dataset on the antimicrobial resistance rates (AMRs) of S. maltophilia ever documented in Saudi Arabia and its neighbouring regions.Recently, the detection rate of S. maltophilia within healthcare facilities has continuously increased 15 .Hospital-acquired infections (HAI) caused by S. maltophilia have also been on an increase, particularly in immunocompromised individuals 2,5 .Consequently, there is a growing need to comprehensively investigate into the risk factors associated with this pathogen, prompting concerns within the medical community.Moreover, relatively few studies have been conducted on S. maltophilia clinical isolates in Saudi Arabia before to and during the COVID-19 pandemic, and this is one of them.
Therefore, this retrospective study conducted a comprehensive analysis over a period of 19 years, including 4466 patients with S. maltophilia.The current study collected clinical data from several hospital wards, with the majority of the study patients originating in the ICUs, followed by the cardiology wards.These results are not unforeseen; given that previous studies conducted in KFMC in Riyadh (2022) and KKUH (2012) have similarly reported the majority of S. maltophilia isolates were from patients admitted in the ICUs 16,17 .By contrast, our results contradicted the findings of the KFMC (2022) 17 study and showed a significant correlation between the prevalence of S. maltophilia isolates between ICU and non-ICU patients before and during the COVID-19 pandemic.The increased rates of S. maltophilia isolates during the COVID-19 pandemic could be attributed to factors such as prolonged hospital stays that have been associated with a higher risk of S. maltophilia infections, broad-spectrum antibiotic use which has been linked to the selection of this pathogen, mechanical ventilation, and the use of invasive medical devices.Therefore, stringent infection control measures and judicious use of antibiotics are crucial to mitigate this risk 15,18,19 .To the best of our knowledge, no studies have been conducted  The increasing prevalence of the isolation of this bacterium is consistent with global reports identifying it as an emerging opportunistic pathogen 15,20,21 .This trend may be attributed to the advancements in detection methods, the susceptibility of immunocompromised patients to S. maltophilia infections, and its ability to exhibit resistance to a broad spectrum of antimicrobial agents.From a global standpoint, S. maltophilia is a major contributor to infections in ICU patients, as evidenced by research conducted in Greece and Spain in 2023 22 , which included 103 non-COVID-19 patients.Likewise, a systematic review conducted in 2022 23 further confirmed the prevalence of this pathogen among ICU patients.
Equally important, according to the World Health Organisation (WHO), S. maltophilia is one of the most common MDR pathogens found in healthcare facilities 24 .The use of SXT and LVX has been widely regarded as the primary approach for antimicrobial therapy in cases of S. maltophilia infections 25 .Due to the remarkable grade of intrinsic or/and acquired antibacterial resistance in S. maltophilia, therapeutic options are limited 26 .Our study revealed a high prevalence of resistance among S. maltophilia isolates towards ceftazidime (72.5%),LVX (56%), and SXT (14.05%).In a study conducted at the KFMC in 2022, 62.1% of S. maltophilia isolates exhibited resistance to ceftazidime.In addition, 14.8% of the isolates were resistant to LVX, whereas 4.1% were resistant to SXT.In another study conducted at KKUH in 2012, 57.21% of S. maltophilia isolates were resistant to ceftazidime, whereas 9.45% were resistant to SXT.The findings presented in this study suggest a notable rise in the ceftazidime resistance rate, perhaps attributable to the widespread and prolonged use of this antibiotic in recent years.Propitiously, SXT continues to demonstrate efficacy as an empirical treatment for infections caused by S. maltophilia.However, the increasing prevalence of resistance to SXT, which has traditionally been the preferred medication for treating S. maltophilia infections, is a matter of worry.Similarly, in a study conducted between 2006 and 2016, the resistance of 130 S. maltophilia isolates to SXT was examined in several centres in the United States.The results revealed resistance rates, ranging from 4 to 21%.The rate of resistance to ceftazidime throughout the specified period ranged from 57 to 84% 25 .A meta-analysis revealed that the areas outside the Eastern Mediterranean Region (EMR) and the Americas Region (AMR) reported the greatest global rates of resistance to SXT, reaching 20%.Comparatively, the resistance rate of EMR was 4.5%, whereas that of AMR was 13.1%.Additionally, ceftazidime has a substantial worldwide resistance rate of 65.1%, which is consistent with the findings of our study 14 .Moreover, when taken alongside other antibiotics, ceftazidime is an effective therapy for infections caused by S. maltophilia 27 .Likewise, a separate systematic review showed that the prevalence rates of S. maltophilia resistance to SXT were 43.82% in Asia, 30.33% in Europe, 23.59% in the Americas, and 2.24% in Africa.In comparison, the rates of resistance to LVX were 44.11%, 26.47%, 27.94%, and 1.47% in the same regions, respectively 21 .The same study reported that the global prevalence rates of LVX and SXT resistance were 14.4% and 9.2%, respectively.Concerningly, the rate of SXT resistance observed in our study was 14.05%, which surpasses both the global rate and China's rate of 14.03%, the latter being the highest reported worldwide 20 .On the contrary, Africa had the lowest S. maltophilia antibiotic resistance rates, perhaps owing to the fewer isolates were identified and/or tested 15,21 .One potential factor contributing to the increased resistance rates of S. maltophilia to LVX is the similarity in the efficacy of LVX and SXT, along with a comparatively lower incidence of adverse effects associated with LVX 15 .This favourable risk-benefit profile positions LVX as the preferred treatment for many patients, hence increasing its likelihood of being overused or misused.Notably, most regional clinical laboratories use automated instruments to determine the minimum inhibitory concentrations (MICs) of SXT, which, according to certain studies, were less accurate compared with alternative approaches, such as disc diffusion.Thus, further investigation is required to establish the present resistance status of SXT 25,28 .
Further, our study revealed that the number of ICU patients with S. maltophilia infections increased during the COVID-19 pandemic (2019, 2020, and 2021).Hence, our data contradict the conclusions drawn by the KFMC (2022) study and demonstrate a significant association between the occurrence of S. maltophilia isolates between patients in ICU and non-ICU settings before and during the COVID-19 pandemic.Globally, two studies conducted in China during the pandemic yielded data consistent with our own findings.These studies indicated that S. maltophilia was among the primary causes of coinfection among COVID-19 patients in the ICU.These findings suggest an increase in S. maltophilia infections during the pandemic period 29,30 .Once again, S. maltophilia has been demonstrated its role as an opportunistic pathogen in individuals with many chronic conditions and compromised immune systems.
Another key point, the Prophet package of R software was used to forecast the future number of isolates to be detected.Our findings showed a positive association between the number of S. maltophilia cases from 2004 to 2022 and the linear regression analysis.The coefficient of estimation (R 2 ) was 0.65, suggesting a strong correlation.Additionally, the P value was < 0.001, further supporting the significance of the observed increase in the number of cases.According to this model, the rate of increase in S. maltophilia isolates is estimated to reach 15.08% [95% CI 12.58-17.59%]by 2030.As a result, it is imperative for health authorities worldwide, as well as in our region, to be vigilant and prepared to address this issue.The need for action is supported by several studies that have confirmed a concurrent increase in antibiotic resistance rates.
This study is valuable for two reasons.First, it represents pioneering research solely focused on S. maltophilia isolates and reaffirms prior observations regarding the escalating detection rate within 19 years, the concerning AMR rates, the effects of the COVID-19 pandemic, and the predicted future ascendancy of infection up to the year 2030.Second, when comparing the aforementioned rates with the global data, it becomes evident that the analysis of the most extensively reported number of S. maltophilia infections demonstrates significantly elevated levels of antibiotic resistance.However, this study has a few limitations that must be acknowledged.The data were collected over a long period (2004-2022); therefore, further analysis that involved classification by isolate type and patient subgroup was not possible.Additionally, the precise patterns of MDRs could not be monitored.The numbers of S. maltophilia isolate and AST findings may also have been affected by the various bacterial identification techniques employed from 2004 to the present day.
In conclusion, the antibiotic resistance rates of S. maltophilia are high and increasing.The alarmingly high rates of resistance to SXT (14.05%),LVX (56%), and ceftazidime (72.5%) are particularly concerning.According to the model used in this study, the prevalence of S. maltophilia detection is expected to increase continuously until 2030, which is supported by the present data.As a result, we encourage immediate measures to be taken on a global scale to address this growing issue with the assistance of healthcare authorities in establishing priorities and tracking the rise in infections and the scarcity of readily accessible treatments.

Figure 4 .
Figure 4.The incidence of S. maltophilia infections among patients in both ICU and non-ICU settings, with a specific focus on the observed increase in S. maltophilia detection rates during the COVID-19 pandemic (2019, 2020, and 2021) in comparison to the rates seen prior and after the pandemic.

Figure 5 .
Figure 5. (a) Significant linear regression of S. maltophilia cases identified from 2004 to 2022.(b) The forecast model, developed using the Prophet package in the R program, gives a projection of forthcoming instances until 2030, revealing an upward trend in the number of cases.

Table 1 .
Distribution of S. maltophilia isolates among different hospital wards.a Other hospital departments.

Table 2 .
The overall susceptibility rate of selected antibiotics that have been used from 2004 to 2022.Each value in the cell represents the mean susceptibility rate and the range (max-min).*Please note that not all antibiotics were accessible during the 19-year period.NT not tested.**Percentage of the total collected samples (4466).